Recent work in our laboratory has demonstrated that certain drugs may be attached to well-defined "carrier" molecules and still retain the ability to bind to the receptor site and effect biological activity. This synthetic strategy for the attachment of drugs to carriers is termed the "functionalized congener" approach. The "carrier" molecule may be many times larger than the parent drug; indeed there is practically no maximum size limitation for a fully potent analog. Unlike the prodrug approach or the immobilization of drugs for slow release, the "functionalized congener" approach is designed to produce analogs for which no metabolic cleavage step is necessary for activation. Moreover, the attachment of the drug to a "carrier" such as a peptide may result in enhanced affinity at an extracellular receptor site and an improvement in the pharmacological profile of the parent drug. Purine derivatives containing attached chains have been developed as functionalized congeners that either activate or antagonize adenosine receptors, and a similar strategy has been used for ATP receptors. For example, the 2-position of the purine moiety has been identified for attachment of functionalized chains in ATP derivatives as P2X and P2Y receptor agonists. Reporter groups such as fluorescent dyes have been covalently attached resulting in receptor probes of relatively high affinity. A3 adenosine receptors are important in the regulation of CNS, cardiac, inflammatory; and reproductive functions. We have developed the first selective agents for this novel receptor. Selective A3 agonists are effective in the treatment of neuro-degenerative diseases. Antagonists have been proposed to have anti-inflammatory properties. New xanthine and adenosine derivatives are being synthesized, screened for A3-receptor selectivity, and later tested in vivo. We have found flavonoids and dihydropyridines to be suitable structural leads for antagonists at human A3 receptors. Chemical modification of these leads (using a template approach) has resulted in compounds with >37,000-fold selectivity. Site-directed mutagenesis and molecular modeling have been used to characterize the ligand binding site.